Bronchial thermoplasty: A promising therapy, still in its infancy

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Bronchial thermoplasty: A promising therapy, still in its infancy

Author(s)

Amit K. Mahajan, MD, FCCP

D. Kyle Hogarth, MD, FCCP

Treating severe, refractory asthma is an ever-evolving challenge and a major source of frustration for patients and clinicians. Failure of inhaler treatment often results in debilitation of the patient and leads to long-term use of corticosteroids, with their insidious side effects.^1–3

See related article

Most asthma research continues to focus on inhibiting the cytokine cascade to reduce inflammation. However, inflammation is not the only pathophysiologic process underlying asthma.

Bronchial thermoplasty takes a novel approach and offers reason for some optimism.^4–6 The aim of this minimally invasive bronchoscopic procedure is to attenuate bronchoconstriction by reducing airway smooth muscle mass.

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Thomas Gildea and colleagues⁷ review the pathophysiology of asthma and the utility of decreasing airway smooth muscle via bronchial thermoplasty, its logistics, and the clinical trials that led to its approval by the US Food and Drug Administration (FDA) for the treatment of severe refractory asthma.

EVIDENCE FROM CLINICAL TRIALS

After studies in animals showed that bronchial thermoplasty was feasible, several randomized trials in humans—the Asthma Intervention Research (AIR) trial,⁶ the Research in Severe Asthma (RISA) trial,⁸ and the Asthma Intervention Research 2 (AIR2) trial⁹—found that the complication rates were acceptable, quality of life was improved, and health care utilization was reduced after the procedure during a 12- to 36-month period. These study results were essential in paving the way for FDA approval.

AIR2: A randomized controlled trial

The latest study to evaluate bronchial thermoplasty, the AIR2 trial,⁹ was designed with a feature that is used relatively infrequently in trials of invasive procedures: a sham control. A sham procedure can be defined as one performed on control-group participants to ensure that they experience the same incidental effects of the procedure as do participants who actually undergo the procedure.¹⁰

Thus, the patients in the control group received the same medications before and after the procedure, they were taken to the procedure room, and the bronchoscope was actually inserted into their lungs—but thermoplasty was not performed. All of this was done in a double-blind manner: neither the patients nor the physicians caring for them before and after the procedure knew which group they were in.

The aim of this exercise was to reduce bias, namely, the placebo effect, and to reinforce results that depend on subjective symptoms, such as the Asthma Quality of Life Questionnaire (AQLQ) score. Clinical trials in severe asthma are notoriously marred by the placebo effect, resulting in spurious improvements in lung function and symptoms.

The AIR2 trial found a significant reduction in severe exacerbations and emergency department visits, and a clinically meaningful improvement in AQLQ score from baseline at 6, 9, and 12 months in the bronchial thermoplasty group. However, 16 patients needed to be hospitalized after the procedure in the bronchial thermoplasty group, compared with two patients in the sham-procedure group.

The AIR2 trial, through the use of a sham-procedure control group, was able to minimize multiple forms of bias and thus provides the most reliable data for clinicians to extrapolate the good and the bad effects of bronchial thermoplasty.

THE PROCEDURE IS STILL IN ITS INFANCY

With any new therapy, we need to look at the benefits and complications not only in the short term but also the long term, ie, to determine whether the benefit is sustainable.

Long-term data on the benefits and side effects of bronchial thermoplasty have yet to be reported. However, radiofrequency ablation has been used in lung cancer therapy during the past decade, with favorable periprocedure complication profiles. Additionally, 5-year follow-up data have shown superior outcomes in stage I non-small-cell lung cancer survival rates with radiofrequency ablation compared with external-beam radiation.¹¹

Ongoing studies will eventually provide insight on long-term outcomes of bronchial thermoplasty in asthma patients. Until such time, patients who have reached the limits of step-up therapy for severe refractory asthma should be informed that clinicians do not yet have a complete understanding of clinical benefits or sustainability of thermoplasty. Still, confidence in bronchial thermoplasty should be grounded in the simplicity of the procedure, the low short-term complication rates, and the long-term success of comparable medical procedures such as radiofrequency ablation in lung cancer, which utilizes similar technology.

Although this procedure is still in its infancy, the potential for long-term effectiveness in improving pulmonary function and quality of life in patients with severe asthma are undeniable. The body of data supporting its use will continue to evolve and hopefully point the way to better control of severe refractory asthma.

References

Bollet AJ, Black R, Bunim JJ. Major undesirable side-effects resulting from prednisolone and prednisone. J Am Med Assoc 1955; 158:459–463.
Olgaard K, Storm T, van Wowern N, et al. Glucocorticoid-induced osteoporosis in the lumbar spine, forearm, and mandible of nephrotic patients: a double-blind study on the high-dose, long-term effects of prednisone versus deflazacort. Calcif Tissue Int 1992; 50:490–497.
Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671–676.
Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006; 173:965–969.
Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005; 127:1999–2006.
Cox G, Thomson NC, Rubin AS, et al; AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356:1327–1337.
Gildea TR, Khatri SB, Castro M. Bronchial thermoplasty: a new treatment for severe refractory asthma. Cleve Clin J Med 2011; 78:477–485.
Pavord ID, Cox G, Thomson NC, et al; RISA Trial Study Group. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007; 176:1185–1191.
Castro M, Rubin AS, Laviolette M, et al; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.
Simpson JA, Weiner ESC, editors. Oxford English Dictionary. 2nd ed. New York, NY: Oxford University Press; 1989.
Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998; 40:149–154.

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Author and Disclosure Information

Amit K. Mahajan, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

D. Kyle Hogarth, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

Address: D. Kyle Hogarth, MD, FCCP, Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, 5841 South Maryland, MC 6076, Chicago, IL 60637; e-mail dhogarth@uchicago.edu

Dr. Hogarth has disclosed speaking, teaching, and serving as an independent contractor for Asthmatx.

Issue

Cleveland Clinic Journal of Medicine - 78(7)

Publications

Cleveland Clinic Journal of Medicine

Topics

Pulmonology

Page Number

475-476

Sections

Editorial

Author(s)

Amit K. Mahajan, MD, FCCP

D. Kyle Hogarth, MD, FCCP

Author(s)

Amit K. Mahajan, MD, FCCP

D. Kyle Hogarth, MD, FCCP

Author and Disclosure Information

Amit K. Mahajan, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

D. Kyle Hogarth, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

Address: D. Kyle Hogarth, MD, FCCP, Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, 5841 South Maryland, MC 6076, Chicago, IL 60637; e-mail dhogarth@uchicago.edu

Dr. Hogarth has disclosed speaking, teaching, and serving as an independent contractor for Asthmatx.

Author and Disclosure Information

Amit K. Mahajan, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

D. Kyle Hogarth, MD, FCCP
Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, Chicago, IL

Address: D. Kyle Hogarth, MD, FCCP, Section of Pulmonary and Critical Care Medicine, University of Chicago Medical Center, 5841 South Maryland, MC 6076, Chicago, IL 60637; e-mail dhogarth@uchicago.edu

Dr. Hogarth has disclosed speaking, teaching, and serving as an independent contractor for Asthmatx.

Article PDF

media_6589dc7_475.pdf

Article PDF

media_6589dc7_475.pdf

Treating severe, refractory asthma is an ever-evolving challenge and a major source of frustration for patients and clinicians. Failure of inhaler treatment often results in debilitation of the patient and leads to long-term use of corticosteroids, with their insidious side effects.^1–3

See related article

Most asthma research continues to focus on inhibiting the cytokine cascade to reduce inflammation. However, inflammation is not the only pathophysiologic process underlying asthma.

Bronchial thermoplasty takes a novel approach and offers reason for some optimism.^4–6 The aim of this minimally invasive bronchoscopic procedure is to attenuate bronchoconstriction by reducing airway smooth muscle mass.

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Thomas Gildea and colleagues⁷ review the pathophysiology of asthma and the utility of decreasing airway smooth muscle via bronchial thermoplasty, its logistics, and the clinical trials that led to its approval by the US Food and Drug Administration (FDA) for the treatment of severe refractory asthma.

EVIDENCE FROM CLINICAL TRIALS

After studies in animals showed that bronchial thermoplasty was feasible, several randomized trials in humans—the Asthma Intervention Research (AIR) trial,⁶ the Research in Severe Asthma (RISA) trial,⁸ and the Asthma Intervention Research 2 (AIR2) trial⁹—found that the complication rates were acceptable, quality of life was improved, and health care utilization was reduced after the procedure during a 12- to 36-month period. These study results were essential in paving the way for FDA approval.

AIR2: A randomized controlled trial

The latest study to evaluate bronchial thermoplasty, the AIR2 trial,⁹ was designed with a feature that is used relatively infrequently in trials of invasive procedures: a sham control. A sham procedure can be defined as one performed on control-group participants to ensure that they experience the same incidental effects of the procedure as do participants who actually undergo the procedure.¹⁰

Thus, the patients in the control group received the same medications before and after the procedure, they were taken to the procedure room, and the bronchoscope was actually inserted into their lungs—but thermoplasty was not performed. All of this was done in a double-blind manner: neither the patients nor the physicians caring for them before and after the procedure knew which group they were in.

The aim of this exercise was to reduce bias, namely, the placebo effect, and to reinforce results that depend on subjective symptoms, such as the Asthma Quality of Life Questionnaire (AQLQ) score. Clinical trials in severe asthma are notoriously marred by the placebo effect, resulting in spurious improvements in lung function and symptoms.

The AIR2 trial found a significant reduction in severe exacerbations and emergency department visits, and a clinically meaningful improvement in AQLQ score from baseline at 6, 9, and 12 months in the bronchial thermoplasty group. However, 16 patients needed to be hospitalized after the procedure in the bronchial thermoplasty group, compared with two patients in the sham-procedure group.

The AIR2 trial, through the use of a sham-procedure control group, was able to minimize multiple forms of bias and thus provides the most reliable data for clinicians to extrapolate the good and the bad effects of bronchial thermoplasty.

THE PROCEDURE IS STILL IN ITS INFANCY

With any new therapy, we need to look at the benefits and complications not only in the short term but also the long term, ie, to determine whether the benefit is sustainable.

Long-term data on the benefits and side effects of bronchial thermoplasty have yet to be reported. However, radiofrequency ablation has been used in lung cancer therapy during the past decade, with favorable periprocedure complication profiles. Additionally, 5-year follow-up data have shown superior outcomes in stage I non-small-cell lung cancer survival rates with radiofrequency ablation compared with external-beam radiation.¹¹

Ongoing studies will eventually provide insight on long-term outcomes of bronchial thermoplasty in asthma patients. Until such time, patients who have reached the limits of step-up therapy for severe refractory asthma should be informed that clinicians do not yet have a complete understanding of clinical benefits or sustainability of thermoplasty. Still, confidence in bronchial thermoplasty should be grounded in the simplicity of the procedure, the low short-term complication rates, and the long-term success of comparable medical procedures such as radiofrequency ablation in lung cancer, which utilizes similar technology.

Although this procedure is still in its infancy, the potential for long-term effectiveness in improving pulmonary function and quality of life in patients with severe asthma are undeniable. The body of data supporting its use will continue to evolve and hopefully point the way to better control of severe refractory asthma.

Treating severe, refractory asthma is an ever-evolving challenge and a major source of frustration for patients and clinicians. Failure of inhaler treatment often results in debilitation of the patient and leads to long-term use of corticosteroids, with their insidious side effects.^1–3

See related article

Most asthma research continues to focus on inhibiting the cytokine cascade to reduce inflammation. However, inflammation is not the only pathophysiologic process underlying asthma.

Bronchial thermoplasty takes a novel approach and offers reason for some optimism.^4–6 The aim of this minimally invasive bronchoscopic procedure is to attenuate bronchoconstriction by reducing airway smooth muscle mass.

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Thomas Gildea and colleagues⁷ review the pathophysiology of asthma and the utility of decreasing airway smooth muscle via bronchial thermoplasty, its logistics, and the clinical trials that led to its approval by the US Food and Drug Administration (FDA) for the treatment of severe refractory asthma.

EVIDENCE FROM CLINICAL TRIALS

After studies in animals showed that bronchial thermoplasty was feasible, several randomized trials in humans—the Asthma Intervention Research (AIR) trial,⁶ the Research in Severe Asthma (RISA) trial,⁸ and the Asthma Intervention Research 2 (AIR2) trial⁹—found that the complication rates were acceptable, quality of life was improved, and health care utilization was reduced after the procedure during a 12- to 36-month period. These study results were essential in paving the way for FDA approval.

AIR2: A randomized controlled trial

The latest study to evaluate bronchial thermoplasty, the AIR2 trial,⁹ was designed with a feature that is used relatively infrequently in trials of invasive procedures: a sham control. A sham procedure can be defined as one performed on control-group participants to ensure that they experience the same incidental effects of the procedure as do participants who actually undergo the procedure.¹⁰

Thus, the patients in the control group received the same medications before and after the procedure, they were taken to the procedure room, and the bronchoscope was actually inserted into their lungs—but thermoplasty was not performed. All of this was done in a double-blind manner: neither the patients nor the physicians caring for them before and after the procedure knew which group they were in.

The aim of this exercise was to reduce bias, namely, the placebo effect, and to reinforce results that depend on subjective symptoms, such as the Asthma Quality of Life Questionnaire (AQLQ) score. Clinical trials in severe asthma are notoriously marred by the placebo effect, resulting in spurious improvements in lung function and symptoms.

The AIR2 trial found a significant reduction in severe exacerbations and emergency department visits, and a clinically meaningful improvement in AQLQ score from baseline at 6, 9, and 12 months in the bronchial thermoplasty group. However, 16 patients needed to be hospitalized after the procedure in the bronchial thermoplasty group, compared with two patients in the sham-procedure group.

The AIR2 trial, through the use of a sham-procedure control group, was able to minimize multiple forms of bias and thus provides the most reliable data for clinicians to extrapolate the good and the bad effects of bronchial thermoplasty.

THE PROCEDURE IS STILL IN ITS INFANCY

With any new therapy, we need to look at the benefits and complications not only in the short term but also the long term, ie, to determine whether the benefit is sustainable.

Long-term data on the benefits and side effects of bronchial thermoplasty have yet to be reported. However, radiofrequency ablation has been used in lung cancer therapy during the past decade, with favorable periprocedure complication profiles. Additionally, 5-year follow-up data have shown superior outcomes in stage I non-small-cell lung cancer survival rates with radiofrequency ablation compared with external-beam radiation.¹¹

Ongoing studies will eventually provide insight on long-term outcomes of bronchial thermoplasty in asthma patients. Until such time, patients who have reached the limits of step-up therapy for severe refractory asthma should be informed that clinicians do not yet have a complete understanding of clinical benefits or sustainability of thermoplasty. Still, confidence in bronchial thermoplasty should be grounded in the simplicity of the procedure, the low short-term complication rates, and the long-term success of comparable medical procedures such as radiofrequency ablation in lung cancer, which utilizes similar technology.

Although this procedure is still in its infancy, the potential for long-term effectiveness in improving pulmonary function and quality of life in patients with severe asthma are undeniable. The body of data supporting its use will continue to evolve and hopefully point the way to better control of severe refractory asthma.

References

Bollet AJ, Black R, Bunim JJ. Major undesirable side-effects resulting from prednisolone and prednisone. J Am Med Assoc 1955; 158:459–463.
Olgaard K, Storm T, van Wowern N, et al. Glucocorticoid-induced osteoporosis in the lumbar spine, forearm, and mandible of nephrotic patients: a double-blind study on the high-dose, long-term effects of prednisone versus deflazacort. Calcif Tissue Int 1992; 50:490–497.
Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671–676.
Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006; 173:965–969.
Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005; 127:1999–2006.
Cox G, Thomson NC, Rubin AS, et al; AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356:1327–1337.
Gildea TR, Khatri SB, Castro M. Bronchial thermoplasty: a new treatment for severe refractory asthma. Cleve Clin J Med 2011; 78:477–485.
Pavord ID, Cox G, Thomson NC, et al; RISA Trial Study Group. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007; 176:1185–1191.
Castro M, Rubin AS, Laviolette M, et al; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.
Simpson JA, Weiner ESC, editors. Oxford English Dictionary. 2nd ed. New York, NY: Oxford University Press; 1989.
Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998; 40:149–154.

References

Bollet AJ, Black R, Bunim JJ. Major undesirable side-effects resulting from prednisolone and prednisone. J Am Med Assoc 1955; 158:459–463.
Olgaard K, Storm T, van Wowern N, et al. Glucocorticoid-induced osteoporosis in the lumbar spine, forearm, and mandible of nephrotic patients: a double-blind study on the high-dose, long-term effects of prednisone versus deflazacort. Calcif Tissue Int 1992; 50:490–497.
Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA 1999; 282:671–676.
Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006; 173:965–969.
Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005; 127:1999–2006.
Cox G, Thomson NC, Rubin AS, et al; AIR Trial Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007; 356:1327–1337.
Gildea TR, Khatri SB, Castro M. Bronchial thermoplasty: a new treatment for severe refractory asthma. Cleve Clin J Med 2011; 78:477–485.
Pavord ID, Cox G, Thomson NC, et al; RISA Trial Study Group. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007; 176:1185–1191.
Castro M, Rubin AS, Laviolette M, et al; AIR2 Trial Study Group. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181:116–124.
Simpson JA, Weiner ESC, editors. Oxford English Dictionary. 2nd ed. New York, NY: Oxford University Press; 1989.
Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience. Int J Radiat Oncol Biol Phys 1998; 40:149–154.